Over 90% of HIV infections occur in developing countries. In this project the specific objectives are to define the unique epidemiologic, clinical, virologic, and immunologic features of HIV infection in developing countries; to determine the viral kinetics associated with perinatal and heterosexual transmission, and to characterize the molecular strains of HIV throughout the world for infectiousness and the immunologic response to cross-clade vaccines. In collaborative studies we have established cohorts of high-risk individuals in Uganda, Congo, Zambia, Zimbabwe, South Africa, India, China and the U.S. In these cohorts we have characterized the prevalence, incidence, and risk behaviors for HIV infection. In the Rakai district of Uganda we estimated the HIV acquisition rate per coital act among 218 HIV-discordant monogamous couples. The acquisition rate of HIV was 0.0011/act and did not vary significantly by gender, age, pregnancy status, hormonal contraception, reported condom use, or STD diagnosis. Acquisition was significantly associated with current genital ulcer disease in women. No seroconversions occurred among men circumcised at baseline vs. a rate of 0.0013 per act among uncircumcised men. Acquisition increased significantly with higher HIV viral load in the infected partner (0.0001/act < 1700 copies/ml vs. 0.0022/act at > 38,500 copies/ml). HIV acquisition was also associated with HSV-2 seropositivity with an odds ratio of 2.6. In addition, at 5 months post-seroconversion viral load was significantly greater in HSV-2 seropositive compared to HSV-2 seronegative individuals. Thus, HSV-2 infection is associated with HIV acquisition and this interaction of HSV-2 and HIV with subsequent increased viral loads among herpes-positive individuals supports the need for HSV-2 treatment and prophylaxis in infected individuals. We also examined the association between HIV viral load and fertility among women in Rakai. In a nested case-control study the median viral load in HIV infected pregnant women was significantly lower than in HIV infected women who could not become pregnant. Statistically significant reductions in pregnancy were observed in women with viral loads > 100,000 copies/ml, suggesting a strong negative virologic effect on health and fertility. Utilizing these Rakai data, we developed a stochastic simulation model to determine the effect of antiretroviral therapy or vaccines in the reduction of HIV incidence in developing countries. Using DHHS treatment guidelines in the model, antiretroviral therapy alone will have a negligible effect on the spread of the epidemic, although it will provide beneficial effects in many other ways for the individual and the population. In contrast, a preventative vaccine, or a therapeutic vaccine that reduces viral load will dramatically reduce HIV transmission and HIV incidence. However, increased risk behaviors would markedly offset these benefits. In developing countries, co-infection with other viral diseases such as measles may contribute to significant morbidity and mortality among HIV-infected children. We demonstrated that HIV-infected children constitute a significant proportion of children hospitalized with measles, and will shed measles virus for a prolonged period of time. In this population of co-infected individuals, the HIV RNA level is markedly reduced during acute measles and subsequently rises with recovery to baseline levels. Plasma levels of immune activation markers such as soluble CD8, beta-2 microglobulin, soluble IL-2R and TNF-R2 were elevated during the period of reduced plasma HIV RNA. Plasma levels of HIV suppressive factors such as RANTES, IL-10 and MIP-1 alpha were also elevated during the period of acute measles. HIV replication is therefore transiently suppressed during acute measles at a time of intense immune activation, a finding that may provide insight to subsequent control of HIV replication. The significance of these studies is that they provide important epidemiologic, clinical, virologic, and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.